This IPRG aims to explore the biological basis of pathogenesis and progression of non-Hodgkin's lymphomas and to integrate these genetic and molecular studies into prognostic models which will guide the development of future clinical trials. The aims of this component are two fold: to evaluate a molecular assay for minimal residual disease (MRD) for monitoring of patients enrolled on prospective clinical trials, and to investigate the role of antigen (Ag) in lymphomagenesis and tumor progression. The first specific aim involves the application of a PCR- mediated RNase protection assay to the detection of MRD. We intend to determine the predictive value of detecting a clone specific sequence in the peripheral blood and bone marrow of patients with lymphoma at diagnosis and following therapy. Furthermore, we will evaluate the utility this in the examination of residual masses present at the completion of therapy. The second specific aim involves investigation of the role of antigenic selection in the pathogenesis of human lymphoma. We have found that clonal expansion in follicular lymphoma occurs subsequent to antigenic selection as indicated by the pattern of somatic mutation of the productively rearranged variable (V) genes. We plan to extend these studies to examine the hypothesis that Ag is also important in the pathogenesis of de novo diffuse large cell lymphoma (DLCL). Biased VH gene usage suggests the tumor cells might be responding to a restricted set of Ags. We will determine if such a bias exists in VH gene usage in diffuse lymphomas. The second sub-aim is to determine on a molecular basis if these tumors are of germinal center origin. This will be accomplished by comparing the sequence of the productively rearranged V gene to that of the corresponding germline V gene obtained by molecular cloning. Analysis of the pattern of mutation, if any, will allow us to determine if antigenically driven clonal expansion is involved in the pathogenesis of these tumors. Finally, we will further explore the role of Ag in follicular lymphomagenesis.